Method for removing heavy metals from organic compounds

ABSTRACT

A method for removing heavy metals, selected from palladium, tin and nickel, from heavy metal complexes with thiazole compounds in aqueous or alcoholic solution, by precipitation as sulfides, characterised in that such solutions are treated with a water-soluble ammonium, alkaline or alkaline-earth sulfide.

This application is a 371 of PCT/EP98/02629 filed May 4, 1998.

The present invention relates to a method for removing heavy metals fromorganic compounds by precipitation as sulfides and, more particularly,it relates to a method for removing heavy metals from aqueous orhydroalcoholic solutions of organic compounds by precipitation assulfides.

Heavy metals, such as for example palladium, tin and nickel areextensively used in synthetic industrial processes for preparing variousorganic compounds useful in many practical fields.

Palladium is the most commonly used heavy metal, especially in couplingreactions.

Because of the high solubility of palladium or other heavy metalcomplexes, even significant amount of such metals can remain, as hardlyremovable impurities, within organic compounds.

Therefore, in case that the use of such compounds requires a high degreeof purity in terms of heavy metals content, their presence represents aconsiderable drawback from the industrial point of view.

Such drawback appears to be particularly relevant, for example, in thecase of pharmacologically active organic compounds for which it is knownthat heavy metals content must be particularly low.

For a general reference on methods for detecting heavy metals content inpharmacologically active compounds see, for example, The United StatesPharmacopeia, USP 23. NF 18. page 1727 (1995).

In the literature, some processes for removing heavy metals, inparticular from industrial waste effluents, are known.

In the U.S. Pat. No. 4,678,584 (Cx/Oxytech. Inc.) a method for removingpalladium and other heavy metals from waste water or from otherindustrial fluids, by precipitation as sulfide, including the use of analkaline or an alkaline-earth trithiocarbonate as precipitant agent, isdescribed.

Nevertheless the present method appears to be rather tedious as far asthe use of the precipitant reagent is concerned, in its turn prepared byreaction of carbon sulfide with a sulfide or an alkaline oralkaline-earth hydroxide.

In our knowledge, methods for removing palladium or other heavy metalsfrom organic compounds involving the use of a sulfide as precipitantagent have not been described in the literature.

Now we have found and it is the object of the present invention a methodfor removing heavy metals from aqueous or hydroalcoholic solutions oforganic compounds, by precipitation as sulfides, characterised in thatsuch solutions are treated with a water-soluble sulfide.

The present method is easily industrially applied and it allows toremove heavy metals efficaciously under particularly smooth reactionconditions.

Such method appears to be widely applicable to a variety of organicsubstrates and it allows to isolate them with high yield and with aparticularly low content of heavy metals, equal to or lower than 10 ppm.

In the present description, if not differently stated, forhydroalcoholic solution we mean an aqueous solution containing C₁-C₄lower alcohols, optionally in admixture.

In the hydroalcoholic solution specific alcohols are, for example,methanol, ethanol, isopropanol, n.butanol or mixture thereof.

Preferably, the hydroalcoholic solution comprises methanol, ethanol ortheir mixture.

The water:alcohol weight ratio in the hydroalcoholic solution ispreferably comprised between 1:4 and an upper limit of 100% in water.

The removal of heavy metals, according to the present method, isdirectly carried out on the aqueous or hydroalcoholic solutions of theorganic compounds by their treatment with a soluble sulfide such as, forexample, ammonium or an alkaline or alkaline-earth metal sulfide.

Specific usable alkaline or alkaline-earth sulfides are, for example,sodium, lithium, potassium, calcium and magnesium sulfide.

Preferably sodium sulfide is used.

Such compounds are easily disposable and commercially available.

According to the method object of the present invention the selectedsulfide is added to the organic compound solution both as solid and,alternatively, as aqueous solution.

Therefore, in that last case, a preformed solution of the selectedsulfide will be added to the aqueous or hydroalcoholic solution of theorganic compound.

It is evident to the man skilled in the art that the amount of thesulfide to be used depends on the amount of the heavy metal to beremoved.

Preferably, the molar ratio sulfide:heavy metal is between 1:1 and100:1.

From an industrial view-point, amounts of sulfide even greater aresimilarly effective but useless.

The suspension obtained by addition of the sulfide to the organiccompound solution containing the heavy metal, is kept under stirring atthe selected temperature and time.

The resultant heavy metal insoluble sulfide is then easily removed fromthe reaction medium by filtration, according to conventional methods.

The method object of the present invention is widely applicable todifferent organic compounds soluble in water or in the abovehydroalcoliolic solutions.

In view of the foregoing, it is evident to the man skilled in the artthat the present method is applicable to the removal of many heavymetals such as, for example, tin, palladium, or other transition metalsable to form insoluble sulfides.

More particularly, the current method is applicable to the removal ofone or more heavy metals present within organic compounds.

Preferably, the method object of the present invention is used to removepalladium.

For a general reference about the use of palladium in synthetic organicprocesses see, for example, Jiro Tsuji, Palladium Reagents andCatalysts, John Wiley & Sons (1995).

In particular, palladium is extensively used as catalyst, both inheterogeneous and homogenous catalysis processes.

Catalysts based on palladium in homogenous catalysis processes are, forexample, the complexes formed by palladium(0) or palladium(II) in thepresence of suitable ligands. in particular triphenylphosphine.

For a general reference about the use of said catalysts see, forexample, Chem. Rev. 1995, 95, 2457-2483 and the already mentioned“Palladium Reagents and Catalysts”.

The use of such catalysts implies that even relevant quantities of saidmetal remain in solution, in the reaction medium, as palladium(0) orpalladium(II).

Therefore, the isolated reaction products will still contain hardlyremovable amounts of palladium.

In the International patent application N^(o) 97/07024 entitled “Processfor the preparation of heteroaryl-phenylalanines” in the name of thesame applicant, a process for the preparation ofheteroaryl-phenylalanines of formula

wherein

R is a hydrogen atom, a C₁-C₄ linear or branched alkyl group or a benzylgroup;

Het is an optionally substituted 5 or 6 member aromatic heterocyclicgroup with 1 or 2 heteroatoms selected among nitrogen, oxygen andsulfur;

comprising the cross-coupling reaction between a phenylalaninederivative and a heteroaryl-zinc halide, in the presence of apalladium(0) based catalyst, is described.

The resultant compounds of formula I can be used as intermediates forthe synthesis of pharmacologically active derivatives.

Therefore, in a preferred embodiment, the method object of the presentinvention is used for removing palladium from the aqueous orhydroalcoholic solutions of heteroaryl-phenylalanines of formula I,optionally as acid addition salts, described in the above-mentionedInternational patent application.

In a preferred embodiment of the process object of the presentinvention, a suitable amount of the selected sulfide in aqueous solutionis added to an appropriate amount of an aqueous or hydroalcoholicsolution of the organic compound, for example a compound preparedaccording to a palladium catalysed cross-coupling process.

The resultant suspension is kept under vigorous stirring at roomtemperature for the selected time.

Subsequently, the formed palladium sulfide is removed by filtrationthrough a celite pad.

By working according to standard isolation techniques, for example byextraction in the presence of an organic solvent, separation of thephases and removal of the organic phase solvent, the desired compound isobtained with high yield and with a palladium content equal to or lowerthan 10 ppm.

The so treated organic compounds can for example be used directly assuch, or as synthetic intermediates, for the preparation ofpharmacologically active derivatives.

The method object of the present invention is easily industriallypracticable and allows to remove palladium and other heavy metals fromorganic compounds in aqueous or hydroalcoholic solutions efficaciously,by employing commonly used and easily disposable precipitant reagents,as the above cited sulfides.

Besides, such a method is carried out under smooth reaction conditionsand can be widely applied to a variety of organic substrates.

With the aim to illustrate the present invention the following examplesare now given.

EXAMPLE 1 Removal of palladium from 4-(2-thiazolyl)-L-phenylalaninemethyl ester dihydrochloride in the presence of sodium sulfidenonahydrate

Sodium sulfide nonahydrate (15 g. 0.06 moles) and charcoal (35 g) wereadded to a solution of 4-(2-thiazolyl)-L-phenylalanine methyl esterdihydrochloride (821 g 2.14 moles) in water (1.6 l), prepared asdescribed in the International patent application N^(o) 97/07024 in thename of the same applicant, kept under nitrogen at room temperature.

The suspension was kept under stirring at a temperature of 20-25° C. for30 minutes and, subsequently, after addition of celite (20 g) andfiltration, the residue was washed with water (2×0.1 l).

Toluene (1.3 l) and a 28% ammonium hydroxide aqueous solution (0.45 l)were added to the resultant yellow-orange aqueous solution up to pH 8.keeping the temperature at 20-25° C.

The mixture was kept under stirring for 30 minutes at room temperatureand the phases were separated.

The separated organic phase was evaporated under reduced pressure at 60°C. giving 4-(2-thiazolyl)-L-phenylalanine methyl ester (0.52 g: HPLCtitre 94.2%) as solid product with a palladium content lower than 10ppm.

EXAMPLE 2 Removal of palladium from 4-(2-thiazolyl)-L-phenylalaninemethyl ester dihydrochloride in the presence of sodium sulfidenonahydrate and ammonium hydroxide

Sodium sulfide nonahydrate (2.76 g; 0.0115 moles) and after 5 minutes, a30% ammonium hydroxide solution (0.0256 l), up to pH 3-3.5 were added toa solution of 4-(2-thiazolyl)-L-phenylalanine methyl esterdihydrochloride (128.5 g: 0.38 moles) in water (0.257 l). prepared asdescribed in example 1 and containing 2700 ppm of palladium.

After 5 minutes under stirring, decolorizing charcoal (6 g) was addedand after further 15 minutes the suspension was filtered through acelite pad, washing the residue with water (3×0.02 l).

The filtrate, kept under stirring at room temperature. was alkalinisedup to pH 8 by adding potassium hydrogencarbonate (42.2 g) and afterwardsextracted with methytene chloride (200 ml).

The organic phase was dried on sodium sulfate and evaporated to drynessfurnishing 4-(2-thiazolyl)-L-phenyalanine methyl ester (100 g), as oilyresidue with a palladium content lower than 10 ppm.

EXAMPLE 3 Removal of palladium and tin from4-(2-thiazolyl)-L-phenylalanine methyl ester dihydrochloride in thepresence of an aqueous solution of sodium sulfide

A solution of sodium sulfide nonahydrate (50 g; 0.21 moles) in water(0.25 1) was added to a solution of 4-(2-thiazolyl)-L-phenylalaninemethyl ester dihydrochloride (278 g; 0.83 moles) in water (2 l),prepared starting from tin-derivatives in the presence of a palladium(0)based catalyst, as described in the International patent WO 97/24342 inthe name of the same applicant, and containing 690 ppm of tin and 250ppm of palladium.

After 1 hour under stirring at room temperature, the resultantsuspension was filtered on a celite pad, washing the residue with water(3×0.1 l).

The filtrate, kept under stirring at room temperature, was alkalinisedup to pH 8 by adding potassium hydrogencarbonate (200 g) and afterwardsextracted with methylene chloride (1 l and 0.5 l).

Decolorizing earth (50 g) was then added to the combined organic phases,washed with water (0.15 l) and dried on sodium sulfate.

The mixture was filtered under vacuum and the residue was washed withmethylene chloride (3×0.2 l).

The resultant solution was evaporated to dryness giving4-(2-diazolyl)-L-phenylalanine methyl ester (183 g), as oily residuewith a palladium and tin content lower than 10 ppm.

What is claimed is:
 1. A method for removing heavy metals, selected from palladium, tin and nickel, from heavy metal complexes with thiazole compounds in aqueous or alcoholic solution, by precipitation as sulfides, characterised in that such solutions are treated with a water-soluble ammonium, alkaline or alkaline-earth sulfide.
 2. A method according to claim 1 for removing palladium.
 3. A method according to claim 1 wherein the alcoholic solution is an aqueous solution containing C₁-C₄ lower alcohols, optionally in admixture.
 4. A method according to claim 3 wherein the lower alcohols are selected between methanol and ethanol.
 5. A method according to claim 1 wherein the water: alcohol weight ratio in the alcoholic solution is comprised between 1:4 and an upper limit of 100% in water.
 6. A method according to claim 1 wherein the sulfide is sodium sulfide.
 7. A method according to claim 1 wherein the aqueous or alcoholic solutions are treated with the water-soluble sulfide in aqueous solution.
 8. A method according to claim 1 wherein the molar ratio of sulfide; heavy metal is between 1:1 and 100:1.
 9. A method for removing palladium from thiazolyl-phenylalanin of formula

wherein R is a hydrogen atom, a C₁-C₄ linear or branched alkyl group or a benzyl group; Het is an optionally substituted thiazolyl; in aqueous or alcoholic solution, by precipitation as sulfide, characterised in that such solutions are treated with a water-soluble ammonium, alkaline or alkaline-earth sulfide.
 10. A method according to claim 1, wherein the sulfide is selected from the group consisting of sodium sulfide, lithium sulfide, potassium sulfide, calcium sulfide, and magnesium sulfide. 